Polymer systems that undergo phase transitions in response to environmental stimuli such as temperature and pH have been widely investigated for drug delivery, separations, and diagnostics applications. A key temperature-responsive class is based on alkyl acrylamide polymers, especially poly(N-isopropylacrylamide) (pNIPAAm), which undergoes a sharp coil-globule transition and phase separation at its lower critical solution temperature (LCST) in water. This spontaneous process is endothermic and is therefore driven by a gain in entropy associated with the release of hydrophobically-bound water molecules. The LCST of such thermally-sensitive polymers can be tuned to a desired temperature range by copolymerization with a more hydrophilic comonomer (which raises the LCST) or a more hydrophobic comonomer (which lowers the LCST).
pH-Sensitive monomers may also be copolymerized with NIPAAm. For these copolymers, the phase separation can also be triggered by a change in the pH at specific temperatures, such as 37° C. Readily available carboxylic acid monomers, such as acrylic acid (AA) or methacrylic acid (MAA), have been copolymerized with NIPAAm using traditional free radical polymerization techniques to form random copolymers with both temperature- and pH-responsive properties. However, the LCSTs of copolymers increase rapidly with increasing acrylic acid comonomer contents at all pH ranges because acrylic acid is intrinsically more hydrophilic than NIPAAm in both the protonated and unprotonated states. In addition, the critical transitions of pH responsive copolymers of NIPAAm with acrylic acid and methacrylic acid are usually below pH 5.0 due to the low pKa values of poly(acrylic acid) and poly(methacrylic acid). Because of this, it has been a general challenge to design NIPAAm copolymers capable of responding to the physiologically-relevant pHs between 5.0 and 7.4.
The properties of NIPAAm copolymers with the hydrophobic acidic monomers 4-pentenoic acid, 6-acrylaminohexanoic acid, and N-acryloyl-L-phenylalanine have been previously reported. The LCSTs of these copolymers decreased at pH 4.0 and increased at pH 7.4 with increasing the content of comonomer 4-pentenoic acid or 6-acrylaminohexanoic acid.
Hydrogels can be made from stimuli-responsive polymers. Stimuli-responsive hydrogels have earned the reputation of “smart materials” because they are able to change abruptly their volume or properties in response to environmental conditions such as temperature, pH, light, and biomolecules. Among the “smart hydrogel materials,” particular attention has been paid to temperature-sensitive poly(N-isopropylacrylamide) (pNIPAAm) hydrogels. Like certain temperature-responsive polymers, pNIPAAm hydrogels undergo an abrupt phase transition in water upon heating above 32° C., when the hydrophilic extended coils collapse into hydrophobic globules causing the gels to shrink and expel most of the absorbed water. Such phase transition behavior is thermo-reversible. Some copolymer hydrogels of NIPAAm and acidic (e.g., acrylic acid, methacrylic acid) or basic comonomers are known to be both pH-sensitive and temperature-sensitive. These dual pH/temperature responsive hydrogels have a variety of applications in many fields including controlled drug delivery systems, chromatographic separation, cell culture, microfluidic actuators/valves, and biosensors.
Readily available carboxylic acid monomers, such as acrylic acid or methacrylic acid, have been copolymerized with NIPAAm using free radical polymerization to form copolymer hydrogels with dual temperature- and pH-responsive properties. However, the critical transitions of pH/temperature responsive NIPAAm and acrylic acid copolymer hydrogels are usually below pH 4.0 due to the low pKa values of poly(acrylic acid) (pKa≈4.25). One serious concern regarding these hydrogels is that many biomolecules, such as peptides and protein, are not stable at low pH. In addition, an increase of acrylic acid content in the NIPAAm copolymer hydrogel could reduce or even eliminate the temperature sensitivity because the hydrophilic acrylic acid comonomer units break pNIPAAm chain sequences into short, uncooperative network segments and, subsequently, weak thermally-driven hydrophobic aggregation of the pNIPAAm chain. Therefore, NIPAAm and acrylic acid copolymer hydrogels cannot show the abrupt and large volume phase transition in an ideal pH range as required in many applications such as microfluidic actuators/valves and drug delivery devices.
Despite the development of temperature- and pH-sensitive copolymers and hydrogels, a need exists for temperature- and pH-sensitive polymer compositions including temperature- and pH-sensitive copolymers and hydrogels having phase transitions at operationally useful temperature and physiological pH (about 5.0 to about 7.4). The present invention seeks to fulfill this need and provides further related advantages.